(PART THREE OF THREE)

Checkpoint inhibitors have one mission: to wake up the sleeping T cells, and in some people with cancer, they have done this spectacularly well. But right now, they don’t help more than a fraction of patients. In other words, for every extraordinary responder – a man whose metastases in the liver and brain simply melt away, whose PSA drops from the thousands to undetectable – there are many times more men who don’t get any better.

Doctors and scientists desperately want to change this.

A brilliant scientist and PCF-funded investigator named Jim Allison was the first to discover molecules on T cells called checkpoints. He figured out that these molecules were putting T cells into an induced coma, stopping them from carrying out their mission as assassins of cancer cells, and he worked to develop the first checkpoint-inhibiting drug, ipilimumab, which has had great success in treating some cancers, particularly melanoma – but not prostate cancer.

What are immune checkpoints and why does inhibiting them help fight cancer? Chuck Drake, M.D., Ph.D., director of genitourinary oncology and the associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center, explains: “When a T cell moves into tissue, as part of that normal process of activation, it installs a brake.” It doesn’t necessarily apply the brake; it just has one ready to go. One of those brakes is a molecule called PD-1, which sits right on the surface of the T cell. “Many tumors have T cells inside them, but they’re not working, because they have PD-1 on their surface.” The T cell with the PD-1 is just sitting there. But cancer cells make sure that cell isn’t going to move by adding a molecule called PD-L1. “That’s the foot on the brake. PD-L1 binds to the PD-1 on the T cell.” Imagine a car with several unpaid parking tickets under the windshield wiper; now imagine a traffic cop coming along and putting a parking boot on the car’s front tire. That car isn’t going anywhere.

So we’ve got our superhero in a stupor, like Superman staggering around or unconscious because Lex Luthor put a big chunk of Kryptonite in the room. But wait! Checkpoint inhibitors are coming to the rescue! “If you block either PD-1 or PD-L1 with a drug, a monoclonal antibody, you can wake up the T cell, take off the boot,” T cells can come roaring in and “do what they were designed to do, which is kill specific cells, including tumor cells.” And this is happening with checkpoint inhibitors in kidney cancer, bladder cancer, melanoma, and lung cancer.

Why doesn’t it work better in prostate cancer? It may have something to do with the number of mutations on the prostate cancer cell. “Some melanomas have over 500 mutations; squamous cell lung cancer can have 200 to 500 mutations; garden variety lung cancer has 150 mutations, kidney cancer has about 70,” says Drake. “But prostate cancer only has about 30 mutations.”

Basically, the more mutations a cancer cell has, the more freakish it looks to the immune system, and the easier it is to recognize as an enemy. Think about any villain in Batman – the Joker, with his green hair and white pancake makeup, for instance. The villainous disguises are really helpful to crime fighters, because they say, “This guy’s dangerous.” But prostate cancers, even the very worst ones, are more like James Bond villains; they don’t look that much different from anybody else.

Timing may be a key factor, too. Drake recalls a study he took part in when he was at Johns Hopkins, of a PD-1 blocker called nivolumab, which has worked well in other cancers. The patients were men with late-stage prostate cancer who had been through ADT and chemotherapy. “We had zero responses in 17 patients.” He recalled some anecdotal evidence from another trial, where a man who was on enzalutamide got Provenge , “his PSA went down to nearly undetectable, and his response lasted a very long time.”

In talking with Julie Graff, the lead investigator on a recent trial where Drake was a co-investigator, “we said, why don’t we try this same thing with pembrolizumab,” another PD-1 blocker. “We wanted to have patients who initially responded to enzalutamide but were progressing, and we didn’t stop the enzalutamide, but added on the pembro. Maybe there’s something funky about tumors progressing on enzalutamide that allows the immune system to recognize them. Whatever it is, maybe it’s better to stay on the enzalutamide and just add the PD-1 blocker.” This strategy worked in a few men who were “exceptional responders.” Drake cites other PCF-funded research from PCF Young Investigator Jennifer Bishop, Ph.D., of Vancouver Prostate Centre, showing that PD-L1 is highly expressed in enzalutamide-resistant prostate cancer. Does this make them more susceptible to a PD-1 blocker?

With PCF Young Investigator Emmanuel Antonarakis, M.D. of Johns Hopkins, Drake is looking at another checkpoint-inhibiting drug (ipilimumab) that blocks a different checkpoint called CTLA-4. “It turns out that within tumors there’s another population of bad guy lymphocytes (white blood cells), called regulatory T cells. These cells have a number of ways to turn off the immune response.”

In addition to blocking CTLA-4, ipilimumab interferes with the function of these regulatory T cells. Which begs the question: “What if you help the killer T cells by blocking PD-1, and at the same time block CTLA-4? In animal models, this works brilliantly,” says Drake. “The first data with melanoma were just magical; tumors shrank in four to six weeks.” Antonarakis and Drake “took turns petitioning the drug company” to do a clinical trial in prostate cancer for several years, with no luck. Then Antonarakis and Hopkins colleague Jun Luo, Ph.D., published an important paper in the New England Journal of Medicine showing that men who have a particular variant androgen receptor, called AR-V7, don’t respond to enzalutamide and abiraterone. “We said, “If we can’t try this with everybody with prostate cancer, can we at least give it to guys who have this anomaly? What if we took AR-V7 patients and treated them with both anti-PD-1 and anti–CTLA-4? Emmanuel wrote the trial, and we will be completely enrolled by the middle of next year. That’s the first trial ever to combine anti-PD-1 and anti-CTLA-4 in prostate cancer. It’s very promising.”

So where do we go from here? Medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, quotes Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” In other words, it’s just getting good. “We are learning so much about the immune system.”

There may be a dozen or more potential checkpoints to block. “We only have drugs for about half, and we have a lot more being investigated.” It may be that for the T cells to eradicate prostate cancer, it will require one or more checkpoint inhibitors, plus one or more vaccines. “When we’ve really got a checkpoint inhibitor that allows these T cells to wake up, PSAs will fall, tumors will melt away. When one of these works, man does it work!”

Immunotherapy-induced changes in how we kill cancer are happening so fast, it’s hard to keep up. In lung cancer, for instance, 30 percent of patients now get a checkpoint inhibitor, nivolumumab, before they get chemotherapy, and about half don’t even need standard chemotherapy. “We don’t even know what some of the antigens are,” says Simons. “We’ve got to make this work for every patient.”